Record: found
Abstract: found
Article: not found

A genomic screen identifies TYRO3 as a MITF regulator in melanoma.

Author(s): Shoutian Zhu, Heiko Wurdak, Yan Wang, Anna Galkin, Haiyan Tao, Jie Li, Costas A Lyssiotis, Feng Yan, Buu P Tu, Loren Miraglia, John Walker, Fanxiang Sun, Anthony Orth, Peter G Schultz, Xu Wu

Publication date: 2009-10-06

Journal: Proceedings of the National Academy of Sciences of the United States of America

Keywords: Animals, Antineoplastic Agents, pharmacology, Apoptosis, drug effects, Blotting, Western, Cell Line, Cell Line, Tumor, Cell Proliferation, Cluster Analysis, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genome-Wide Association Study, methods, Humans, Melanoma, genetics, metabolism, pathology, Melanoma, Experimental, Mice, Mice, Nude, Microphthalmia-Associated Transcription Factor, Oligonucleotide Array Sequence Analysis, RNA Interference, RNA, Messenger, Receptor Protein-Tyrosine Kinases, Reverse Transcriptase Polymerase Chain Reaction

Read this article at

ScienceOpenPublisher PMC

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Malignant melanoma is the most aggressive form of cutaneous carcinoma, accounting for 75% of all deaths caused by skin cancers. Microphthalmia-associated transcription factor (MITF) is a master gene regulating melanocyte development and functions as a "lineage addiction" oncogene in malignant melanoma. We have identified the receptor protein tyrosine kinase TYRO3 as an upstream regulator of MITF expression by a genome-wide gain-of-function cDNA screen and show that TYRO3 induces MITF-M expression in a SOX10-dependent manner in melanoma cells. Expression of TYRO3 is significantly elevated in human primary melanoma tissue samples and melanoma cell lines and correlates with MITF-M mRNA levels. TYRO3 overexpression bypasses BRAF(V600E)-induced senescence in primary melanocytes, inducing transformation of non-tumorigenic cell lines. Furthermore, TYRO3 knockdown represses cellular proliferation and colony formation in melanoma cells, and sensitizes them to chemotherapeutic agent-induced apoptosis; TYRO3 knockdown in melanoma cells also inhibits tumorigenesis in vivo. Taken together, these data indicate that TYRO3 may serve as a target for the development of therapeutic agents for melanoma.